Transforming growth factor alpha is a critical mediator of radiation lung injury.
Transforming growth factor alpha is a critical mediator of radiation lung injury.
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DOI：
10.1667/rr13625.1
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发表时间：
2014-09
影响因子：
3.4
通讯作者：
Citrin D
中科院分区：
文献类型：
--
作者：
Chung EJ;Hudak K;Horton JA;White A;Scroggins BT;Vaswani S;Citrin D
肺的放射性纤维化是胸部放射的一种晚期毒性。表皮生长因子（EGF）信号传导先前与放射性肺损伤有关。我们假设TGF-α，一种EGF受体配体，在辐射诱导的肺纤维化中起关键作用。将转化生长因子（TGF-α−/−）缺乏的小鼠和对照C57Bl/ 6J （C57-WT）小鼠分别暴露于每天5次6 Gy的胸部照射下。随访各组小鼠的生存（每组n≥5只）和组织收集（每个品系和时间点n = 3只）。通过马松三色染色和羟脯氨酸含量分析评估辐照肺中胶原积累。ELISA法检测肺组织细胞因子水平。体外观察TGF-α对肺细胞和成纤维细胞增殖及胶原生成的影响。测定体外和体内赖氨酸氧化酶（LOX）的表达和活性。C57-WT小鼠的中位生存期为24.4周，而TGF-α−/−小鼠的中位生存期为48.2周（P = 0.001）。在照射后20周，与TGF-α−/−小鼠或未照射的C57-WT小鼠相比，暴露于辐射的C57-WT小鼠羟脯氨酸含量显著增加（分别为63.0、30.5和37.6µg/肺，P = 0.01）。暴露于辐射的C57-WT小鼠在暴露20周后出现致密的胸膜下纤维化灶，而TGF-α−/−照射小鼠的肺基本没有纤维化灶。C57-WT和TGF-α - / -小鼠辐照后多个时间点肺组织IL-1β、IL-4、TNF-α、TGF-β和EGF浓度相似。C57-WT小鼠肺组织TGF-α在照射后迅速升高，持续20周。TGF-α−/−小鼠LOX的基础表达低于C57-WT小鼠。照射后，所有小鼠的LOX表达和LOX活性均增加，但TGF-α−/−小鼠的LOX表达和活性增加程度较低。TGF-α处理NIH-3T3成纤维细胞可增加细胞增殖、胶原生成和LOX活性。这些研究发现TGF-α是辐射诱导肺损伤的关键介质，也是一种新的治疗靶点。此外，这些数据暗示TGF-α通过TGF-β不依赖赖氨酸氧化酶的激活作为胶原成熟的中介。
Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-α, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-α−/−) and control C57Bl/ 6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ≥ 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson’s trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-α on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-α−/− mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-α−/− mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 µg/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-α−/− mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1β, IL-4, TNF-α, TGF-β and EGF at multiple time points after irradiation were similar in C57-WT and TGF-α−/− mice. TGF-α in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-α−/− mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-α−/− mice. Treatment of NIH-3T3 fibroblasts with TGF-α resulted in increases in proliferation, collagen production and LOX activity. These studies identify TGF-α as a critical mediator of radiation-induced lung injury and a novel therapeutic target in this setting. Further, these data implicate TGF-α as a mediator of collagen maturation through a TGF-β independent activation of lysyl oxidase.